Intracellular protein degradation is a fundamental cellular process which is as important as protein synthesis in the regulation of gene expression. Althrough our understanding of protein degradation is progressing very rapidly, most of the important characteristics of this process have been demonstrated only in normal animals and may not even apply to pathological and physiological situations where overall rates of protein catabolism are altered. Two conditions in which degradative rates are markedly accelerated are diabetes and starvation where proteolysis is increased by 50 degrees-150 degrees in insulin-sensitive tissues. By using a variety of protocols to measure relative rates of protein degradation in intact rats, we intend to determine whether three properties which characterize protein catabolism in normal tissues are also present in diabetes and starvation. With isolated liver cells incubated in vitro, we will define the hormonal and nutritional factors which contribute to the accelerated protein breakdown in diabetes and starvation and study possible mechanisms by which insulin or other factors may alter protein degradative rates. Finally, since degradation of serum proteins is also altered in diabetes and starvation, we will study the characteristics of serum protein catabolism in normal, starved and diabetic animals and investigate the mechanisms by which degradative rates of serum proteins may be regulated.